Gap Prepulse Inhibition Of The Acoustic Startle Research Articles

Characterization of the neural circuitry of the auditory thalamic reticular nucleus and its potential role in salicylate-induced tinnitus.

Subjective tinnitus, the perception of sound without an external acoustic source, is often subsequent to noise-induced hearing loss or ototoxic medications. The condition is believed to result from neuroplastic alterations in the auditory centers, characterized by heightened spontaneous neural activities and increased synchrony due to an imbalance between excitation and inhibition. However, the role of the thalamic reticular nucleus (TRN), a structure composed exclusively of GABAergic neurons involved in thalamocortical oscillations, in the pathogenesis of tinnitus remains largely unexplored. We induced tinnitus in mice using sodium salicylate and assessed tinnitus-like behaviors using the Gap Pre-Pulse Inhibition of the Acoustic Startle (GPIAS) paradigm. We utilized combined viral tracing techniques to identify the neural circuitry involved and employed immunofluorescence and confocal imaging to determine cell types and activated neurons. Salicylate-treated mice exhibited tinnitus-like behaviors. Our tracing clearly delineated the inputs and outputs of the auditory-specific TRN. We discovered that chemogenetic activation of the auditory TRN significantly reduced the salicylate-evoked rise in c-Fos expression in the auditory cortex. This finding posits the TRN as a potential modulatory target for tinnitus treatment. Furthermore, the mapped sensory inputs to the auditory TRN suggest possibilities for employing optogenetic or sensory stimulations to manipulate thalamocortical activities. The precise mapping of the auditory TRN-mediated neural pathways offers a promising avenue for designing targeted interventions to alleviate tinnitus symptoms.

Effectiveness of transcutaneous vagus nerve stimulation (tVNS) on salicylate-induced tinnitus

IntroductionTinnitus is the most common symptom of auditory system disorders. It affects the quality of life of millions of people, but it is still incurable in most cases. Vagus nerve stimulation (VNS) therapy is a potential new treatment for subjective tinnitus. In this study, transcutaneous vagus nerve stimulation (tVNS) combined with tones was utilized to treat salicylate-induced tinnitus since salicylate is a reliable and convenient approach for rapidly inducing tinnitus. MethodsWistar rats were divided into acoustic stimulation alone (AS, n = 6), tVNS alone (n = 6), and tVNS with AS (n = 6) groups for behavioral and electrophysiological tests. They were assessed by auditory brainstem response (ABR), prepulse inhibition (PPI), gap prepulse inhibition of the acoustic startle (GPIAS), social interactions, and aggressive behavior tests at baseline and seven days’ post-salicylate (175 mg/kg, twice a day) injection. ResultsThe inhibition percentage of the GPIAS test was significantly reduced post-salicylate injection in the tVNS and AS alone groups, while it was not significant in the tVNS with AS group. There was no significant difference in the mean percentage of the GPIAS test between the tVNS groups (with or without AS) after salicylate injections. Social interactions were significantly different in the AS alone group pre- and post-salicylate injections, but they were not significant in other groups. Moreover, the results of aggressive behavior tests showed significantly increased post-salicylate injections in the AS alone group, while they were not significant in the tVNS groups (with or without AS). ConclusionsThe current study revealed that the application of tVNS alone produced improved social interaction and mood and alleviated salicylate-induced tinnitus severity. Moreover, combining tVNS with acoustic stimulation can prevent salicylate-induced tinnitus.

Electrophysiological and molecular changes following neuroprotective placental protein administration on tinnitus-induced rats.

Despite 6%-20% of the adult population suffering from tinnitus, there is no standard treatment for it. Placenta extract has been used for various therapeutic purposes, including hearing loss. Here, we evaluate the effect of a novel neuroprotective protein composition (NPPC) extract on electrophysiological and molecular changes in the medial geniculate body (MGB) of tinnitus-induced rats. To evaluate the protein analysis by western blot, the rats were divided into three groups: (1) saline group (intraperitoneal injection of 200 mg/kg saline twice a day for 28 consecutive days, (2) chronic Na-Sal group received sodium salicylate as in the first group, and (3) chronic treatment group (received salicylate 200 mg/kg twice daily for 2 weeks, followed by 0.4 mg NPPC daily from day 14 to day 28). Single-unit recordings were performed on a separate group that was treated as in group 4. Gap-prepulse inhibition of the acoustic startle (GPIAS) and pre-pulse inhibition (PPI) was performed to confirm tinnitus in all groups at the baseline, 14th and 28th days. Western blot analysis showed that the expression of γ-Aminobutyric acid Aα1 subunit (GABA Aα1), N-methyl-d-aspartate receptor subtype 2B (NR2B or NMDAR2B), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors subunit GluR1 (GluR1), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors subunit GluR2 (GluR2) decreased after Na-Sal injection, while NPPC upregulated their expression. MGB units in rats with tinnitus showed decreased spontaneous firing rate, burst per minute, and a spike in a burst. After NPPC administration, neural activity patterns showed a significant positive effect of NPPC on tinnitus. NPPC can play an effective role in the treatment of tinnitus in salicylate-induced rats, and MGB is one of the brain areas involved in these processes. NA.

The human neuroprotective placental protein composition suppressing tinnitus and restoring auditory brainstem response in a rodent model of sodium salicylate-induced ototoxicity

The effect of neuroprotective placental protein composition (NPPC) on the suppression of tinnitus and the restoration of the auditory brainstem response (ABR) characteristics was explored in tinnitus-induced rats. The animals were placed into two groups: (1) the study group, rats received sodium salicylate (SS) at the dose of 200 mg/kg twice a day for two weeks, and then 0.4 mg of the NPPC per day, between the 14th and 28th days, (2) the placebo group, rats received saline for two weeks, and then the NPPC alone between the 14th and 28th days. The gap pre-pulse inhibition of the acoustic startle (GPIAS), the pre-pulse inhibition (PPI), and the ABR assessments were performed on animals in both groups three times (baseline, day 14, and 28). The GPIAS value declined after 14 consecutive days of the SS injection, while NPPC treatment augmented the GPIAS score in the study group on the 28th day. The PPI outcomes revealed no significant changes, indicating hearing preservation after the SS and NPPC administrations. Moreover, some changes in ABR characteristics were observed following SS injection, including (1) higher ABR thresholds, (2) lowered waves I and II amplitudes at the frequencies of 6, 12, and 24 kHz and wave III at the 12 kHz, (3) elevated amplitude ratios, and (4) prolongation in brainstem transmission time (BTT). All the mentioned variables returned to their normal values after applying the NPPC. The NPPC use could exert positive therapeutic effects on the tinnitus-induced rats and improve their ABR parameters.

Susceptibility and mechanism of sodium salicylate-induced tinnitus model in low estrogen rats

Objective: The susceptibility of tinnitus rats with low estrogen level induced by sodium salicylate and the changes of tumor necrosis factor α (TNF-α) in serum were observed to investigate the relationship between tinnitus occurrence and estrogen level. Methods: Forty-two healthy female Wistar rats were randomly divided into control group(n=6), normal group(n=6), sham operation group(n=6) and ovariectomized group(n=24). Control group was intraperitoneally injected with normal saline 200 mg/kg for 14 consecutive days. Normal group, sham operation group and ovariectomized group were intraperitoneally injected with sodium salicylate 200 mg/kg for 14 consecutive days. Before and after sodium salicylate induction, the tinnitus behavior of rats in each group was detected by prepulse inhibition (PPI) and gap pre-pulse inhibition of the acoustic startle (GPIAS) test. Before and after sodium salicylate induction, blood samples were collected from eyeballs of rats in each group, and serum levels of estradiol and TNF-α were detected by ELISA. SPSS 25.0 software was used to analyze the data. Results: (1) Following 14 days of sodium salicylate intervention, there was no significant difference in PPI inhibition rate between groups or within groups(all P>0.05). (2)There was no significant difference in the inhibition rate of GPIAS in the four groups before sodium salicylate injection(F=0.217, P>0.05). With sodium salicylate injected for 14 days, the inhibition rate of GPIAS in ovariectomized group (30.88%±15.40%) was significantly lower than that in the other three groups (44.11%±21.06%, 38.27%±10.92%, 51.59%±11.34%), and the difference was statistically significant(F=3.533, P<0.05). The inhibition rate of GPIAS in ovariectomized group with sodium salicylate injected for 14 days was significantly lower than that before injection, and the difference was statistically significant(t=2.977, P<0.05).There was no significant difference in GPIAS inhibition rate between the other three groups before and after sodium salicylate injection(P>0.05). (3)The level of TNF-α in ovariectomized rats was significantly higher than that in the other three groups, the difference was statistically significant(all P<0.05). With sodium salicylate injection for 14 days, TNF-α level in the ovariectomized group increased more significantly than that in the other three groups, the difference was statistically significant(F=8.045, P<0.05). TNF-α levels increased following salicylate injection in normal group, sham operation group and ovariectomized group, and the differences were statistically significant(t value was -4.843, -4.932 and -5.965 respectively, each P<0.05). There was no significant difference in TNF-α levels before and after normal saline injection in control group(all P>0.05). Conclusion: Low estrogen levels increase susceptibility to sodium salicylate-induced tinnitus. Decreased estrogen levels may increase susceptibility to tinnitus through the increased expression of pro-inflammatory factor TNF-α.

Evidence of Tinnitus Development Due to Stress: An Experimental Study in Rats.

Tinnitus can develop due to, or be aggravated by, stress in a rat model. To investigate stress as a possible causal factor in the development of tinnitus, we designed an animal study that included tinnitus behavior and excitatory/inhibitory neurotransmitter expression after noise exposure as well as restraint stress. An experimental animal study. Wistar rats were grouped according to single or double exposure to noise and restraint stress. The noise exposure (NE) group was subjected to 110 dB sound pressure level (SPL) of 16 kHz narrow-band noise (NBN) for 1 hour, and the restraint stress (RS) group was restrained for 1 hour with or without noise exposure. Gap prepulse inhibition of the acoustic startle (GPIAS) reflex was measured at an NBN of 16 kHz to investigate tinnitus development. Various immunohistopathologic and molecular biologic studies were undertaken to evaluate possible mechanisms of tinnitus development after noise and/or restraint stress. The RS-only group showed a reduced GPIAS response, which is a reliable sign of tinnitus development. In the double-stimulus groups, more tinnitus-development signs of reduced GPIAS responses were observed. The expression of γ-aminobutyric acid A receptor α1 (GABAAR α1) in the hippocampus decreased in the NE│RS group. Increased N-methyl-d-aspartate receptor1 intensities in the NE│RS group and decreased GABAAR α1 intensities in the RS and NE│RS groups were observed in the CA3 region of the hippocampus. Tinnitus appeared to develop after stress alone in this animal study. An imbalance in excitatory and inhibitory neurotransmitters in the hippocampus may be related to the development of tinnitus after acute NE and/or stress. NA Laryngoscope, 131:2332-2340, 2021.

Noise Exposure Alters Glutamatergic and GABAergic Synaptic Connectivity in the Hippocampus and Its Relevance to Tinnitus.

Accumulating evidence implicates a role for brain structures outside the ascending auditory pathway in tinnitus, the phantom perception of sound. In addition to other factors such as age-dependent hearing loss, high-level sound exposure is a prominent cause of tinnitus. Here, we examined how noise exposure altered the distribution of excitatory and inhibitory synaptic inputs in the guinea pig hippocampus and determined whether these changes were associated with tinnitus. In experiment one, guinea pigs were overexposed to unilateral narrow-band noise (98 dB SPL, 2 h). Two weeks later, the density of excitatory (VGLUT-1/2) and inhibitory (VGAT) synaptic terminals in CA1, CA3, and dentate gyrus hippocampal subregions was assessed by immunohistochemistry. Overall, VGLUT-1 density primarily increased, while VGAT density decreased significantly in many regions. Then, to assess whether the noise-induced alterations were persistent and related to tinnitus, experiment two utilized a noise-exposure paradigm shown to induce tinnitus and assessed tinnitus development which was assessed using gap-prepulse inhibition of the acoustic startle (GPIAS). Twelve weeks after sound overexposure, changes in excitatory synaptic terminal density had largely recovered regardless of tinnitus status, but the recovery of GABAergic terminal density was dramatically different in animals expressing tinnitus relative to animals resistant to tinnitus. In resistant animals, inhibitory synapse density recovered to preexposure levels, but in animals expressing tinnitus, inhibitory synapse density remained chronically diminished. Taken together, our results suggest that noise exposure induces striking changes in the balance of excitatory and inhibitory synaptic inputs throughout the hippocampus and reveal a potential role for rebounding inhibition in the hippocampus as a protective factor leading to tinnitus resilience.

The gap prepulse inhibition of the acoustic startle (GPIAS) paradigm to assess auditory temporal processing: Monaural versus binaural presentation.

The Gap Prepulse Inhibition of the Acoustic Startle Reflex (GPIAS) is a paradigm used to assess auditory temporal processing in both animals and humans. It consists of the presentation of a silent gap embedded in noise and presented a few milliseconds before a startle sound. The silent gap produces the inhibition of the startle reflex, a phenomenon called gap-prepulse inhibition (GPI). This paradigm is also used to detect tinnitus in animal models. The lack of inhibition by the silent gaps is suggested to be indicative of the presence of tinnitus "filling-in" the gaps. The current research aims at improving the GPIAS technique by comparing the GPI produced by monaural versus binaural silent gaps in 29 normal-hearing subjects. Two gap durations (5 or 50ms), each embedded in two different frequency backgrounds (centered around 500 or 4 kHz). Both low- and high- frequency narrowband noises had a bandwidth of half an octave. Overall, the startle magnitude was greater for the binaural versus the monaural presentation, which might reflect binaural loudness summation. In addition, the GPI was similar between the monaural and the binaural presentations for the high-frequency background noise. However, the GPI was greater for the low-frequency background noise for the binaural, compared to the monaural, presentation. These findings suggest that monaural GPIAS might be more suited to detect tinnitus compared to the binaural presentation.

A Mouse Model of Tinnitus Using Gap Prepulse Inhibition of the Acoustic Startle in an Accelerated Hearing Loss Strain.

To develop a mouse model for temporary and persistent tinnitus using the gap startle paradigm. Behavioral animal models for tinnitus are classified into conditioning- and reflex-based types. Gap prepulse inhibition of the acoustic startle (GPIAS) is based on the acoustic startle modification by a silent gap and gap detection deficit caused by tinnitus gap filling. We used C57BL/6J mice inherently susceptible to hearing loss and potentially predisposed to tinnitus. They were divided into the control, salicylate-induced tinnitus, and noise-induced tinnitus groups. Mice were tested with the auditory brainstem response at four frequencies (8, 16, 24, and 32 kHz) and GPIAS in three carrier conditions, 16 and 24 kHz narrow band noises (NBNs) and broadband noise, at multiple time points before and after treatment. The ratio between the gap startle and no-gap startle amplitudes was analyzed by a repeated measures design. In addition, the number of tinnitus-positive mice meeting a specified criterion was counted. Salicylate/unilateral noise trauma resulted in temporary/permanent tinnitus evidenced by GPIAS reduction. GPIAS reduction was the most significant at 16 kHz NBN among the three carriers in both tinnitus groups. Control mice also showed good gap detection performance at 16 kHz NBN, which is in the most sensitive hearing range in mice. The GPIAS test in C57BL/6J mice was very reliable at 16 kHz NBN. This tinnitus model developed in the mouse strain of accelerated hearing loss can be used with two options of temporary and persistent tinnitus.

Objective Verification of Acute Tinnitus and Validation of Efficacy of Systemic Steroids in Rats.

BackgroundThis study was performed to identify acute tinnitus and evaluate the efficacy of steroids for noise-induced acute tinnitus by measuring the gap-prepulse inhibition of the acoustic startle (GPIAS) value in an animal model.MethodsNineteen rats (the noise group [n = 7] and the noise + dexamethasone [DEX] group [n = 12]) were exposed to narrow-band noise centered at 16 kHz from a sound generator for 4 hours. The noise + DEX group received intraperitoneal steroid administration daily for 5 days (1.5 mg/kg/day) after completing noise exposure. Auditory brainstem response and GPIAS value were measured just prior to, and 1 day after noise exposure and on days 1 and 10 days after completing steroid administration. The changes in cochlear structure were evaluated by histological analysis.ResultsThe threshold shift was checked 1 and 10 days after intraperitoneal steroid injection, and no differences in threshold shift were observed between the two groups in each frequency except for 32 kHz 1 day after steroid injection. The mean GPIAS value in the noise + DEX group (36.4% ± 14.1%) was significantly higher than that in the noise group (16.4% ± 18.8%) 10 days after intraperitoneal steroid administration (P = 0.017). There were no pathological changes associated with noise trauma in the two groups as determined on hematoxylin and eosin and immunohistochemical staining.ConclusionAn acute tinnitus model with minimal structural changes by noise exposure was set up, and used to verify tinnitus objectively by measuring the GPIAS value. Steroid therapy for control of tinnitus was validated in this animal model.

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs.

Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap-prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude-intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2-weeks following noise-exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20-60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus-specific changes were particularly prominent in hippocampal synapse-rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus-specific changes occurred in synapse-rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.

Glutamatergic Projections to the Cochlear Nucleus are Redistributed in Tinnitus

Tinnitus alters auditory–somatosensory plasticity in the cochlear nucleus (CN). Correspondingly, bimodal auditory–somatosensory stimulation treatment attenuates tinnitus, both in animals and humans (Marks et al., 2018). Therefore, we hypothesized that tinnitus is associated with altered somatosensory innervation of the CN. Here, we studied the expression of vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) in the CN, which reveals glutamatergic projections from the cochlea as well as somatosensory systems to this brainstem auditory center.Guinea pigs were unilaterally exposed to narrowband noise and behaviorally tested for tinnitus using gap-prepulse inhibition of the acoustic startle. Following physiological and behavioral measures, brain sections were immunohistochemically stained for VGLUT1 or VGLUT2. Puncta density was determined for each region of the ipsilateral and contralateral CN.Tinnitus was associated with an ipsilateral upregulation of VGLUT2 puncta density in the granule cell domain (GCD) and anteroventral CN (AVCN). Furthermore, there was a tinnitus-associated interaural asymmetry for VGLUT1 expression in the AVCN and deep layer of the dorsal CN (DCN3), due to contralateral downregulation of VGLUT1 expression. These tinnitus-related glutamatergic imbalances were reversed upon bimodal stimulation treatment.Tinnitus-associated ipsilateral upregulation of VGLUT2-positive projections likely derives from somatosensory projections to the GCD and AVCN. This upregulation may underlie the neurophysiological hallmarks of tinnitus in the CN. Reversing the increased ipsilateral glutamatergic innervation in the CN is likely a key mechanism in treating tinnitus.

Differential Neural Responses Underlying the Inhibition of the Startle Response by Pre-Pulses or Gaps in Mice.

Gap pre-pulse inhibition of the acoustic startle (GPIAS) is a behavioral paradigm used for inferring the presence of tinnitus in animal models as well as humans. In contrast to pre-pulse inhibition (PPI), the neural circuitry controlling GPIAS is poorly understood. To increase our knowledge on GPIAS, a comparative study with PPI was performed in mice combining these behavioral tests and c-Fos activity mapping in brain areas involved in the inhibition of the acoustic startle reflex (ASR). Both pre-pulses and gaps efficiently inhibited the ASR and abolished the induction of c-Fos in the pontine reticular nucleus. Differential c-Fos activation was found between PPI and GPIAS in the forebrain whereby PPI activated the lateral globus pallidus and GPIAS activated the primary auditory cortex. Thus, different neural maps are regulating the inhibition of the startle response by pre-pulses or gaps. To further investigate this differential response to PPI and GPIAS, we pharmacologically disrupted PPI and GPIAS with D-amphetamine or Dizocilpine (MK-801) to target dopamine efflux and to block NMDA receptors, respectively. Both D-amp and MK-801 efficiently decreased PPI and GPIAS. We administered Baclofen, an agonist GABAB receptor, but failed to detect any robust rescue of the effects of D-amp and MK-801 suggesting that PPI and GPIAS are GABAB-independent. These novel findings demonstrate that the inhibition of the ASR by pre-pulses or gaps is orchestrated by different neural pathways.

GLAST Deficiency in Mice Exacerbates Gap Detection Deficits in a Model of Salicylate-Induced Tinnitus.

Gap detection or gap pre-pulse inhibition of the acoustic startle (GPIAS) has been successfully used in rat and guinea pig models of tinnitus, yet this system has been proven to have low efficacy in CBA mice, with low basal GPIAS and subtle tinnitus-like effects. Here, we tested five mouse strains (CBA, BalbC, CD-1, C57BL/6 and 129sv) for pre-pulse inhibition (PPI) and gap detection with varying interstimulus intervals (ISI) and found that mice from a CBA genetic background had the poorest capacities of suppressing the startle response in the presence of a pre-pulse or a gap. CD-1 mice displayed variable responses throughout all ISI. Interestingly, C57BL/6, 129sv and BalbC showed efficient suppression with either pre-pulses or gaps with shorter ISI. The glutamate aspartate transporter (GLAST) is expressed in support cells from the cochlea and buffers the excess of glutamate. We hypothesized that loss of GLAST function could sensitize the ear to tinnitus-inducing agents, such as salicylate. Using shorter ISI to obtain a greater dynamic range to assess tinnitus-like effects, we found that disruption of gap detection by salicylate was exacerbated across various intensities of a 32-kHz narrow band noise gap carrier in GLAST knockout (KO) mice when compared to their wild-type (WT) littermates. Auditory brainstem responses (ABR) and distortion-product otoacoustic emission (DPOAE) were performed to evaluate the effects on hearing functions. Salicylate caused greater auditory threshold shifts (near 15 dB) in GLAST KO mice than in WT mice across all tested frequencies, despite similarly reduced DPOAE. Despite these changes, inhibition using broad-band gap carriers and 32 kHz pre-pulses were not affected. Our study suggests that GLAST deficiency could become a useful experimental model to decipher the mechanisms underlying drug-induced tinnitus. Future studies addressing the neurological correlates of tinnitus in this model could provide additional insights into the mechanisms of tinnitus.

Increased Synchrony and Bursting of Dorsal Cochlear Nucleus Fusiform Cells Correlate with Tinnitus.

Tinnitus, a phantom auditory percept, is encoded by pathological changes in the neural synchrony code of perceptual processing. Increased cross-unit synchrony and bursting have been linked to tinnitus in several higher auditory stations but not in fusiform cells of the dorsal cochlear nucleus (DCN), key brainstem neurons in tinnitus generation. Here, we demonstrate increased synchrony and bursting of fusiform cell spontaneous firing, which correlate with frequency-specific behavioral measures of tinnitus. Thus, the neural representation of tinnitus emerges early in auditory processing and likely drives its pathophysiology in higher structures.

The gap‐startle paradigm to assess auditory temporal processing: Bridging animal and human research

The gap-prepulse inhibition of the acoustic startle (GPIAS) paradigm is the primary test used in animal research to identify gap detection thresholds and impairment. When a silent gap is presented shortly before a loud startling stimulus, the startle reflex is inhibited and the extent of inhibition is assumed to reflect detection. Here, we applied the same paradigm in humans. One hundred and fifty-seven normal-hearing participants were tested using one of five gap durations (5, 25, 50, 100, 200 ms) in one of the following two paradigms-gap-embedded in or gap-following-the continuous background noise. The duration-inhibition relationship was observable for both conditions but followed different patterns. In the gap-embedded paradigm, GPIAS increased significantly with gap duration up to 50 ms and then more slowly up to 200 ms (trend only). In contrast, in the gap-following paradigm, significant inhibition-different from 0--was observable only at gap durations from 50 to 200 ms. The finding that different patterns are found depending on gap position within the background noise is compatible with distinct mechanisms underlying each of the two paradigms.

Partial to complete suppression of unilateral noise-induced tinnitus in rats after cyclobenzaprine treatment.

Some forms of tinnitus are believed to arise from abnormal central nervous system activity following a single or repeated noise exposure, for which there are no widely accepted pharmacological treatments. One central site that could be related to tinnitus awareness or modulation is the locus coeruleus, a brainstem structure associated with stress, arousal, and attention. In the present study, we evaluated the effects of cyclobenzaprine, a drug known to act on the rat locus coeruleus, on noise-induced tinnitus using Gap Prepulse Inhibition of the Acoustic Startle (GPIAS). In untreated rats, brief silent gaps presented prior to a 5-10-kHz bandpass startling stimulus produced robust GPIAS. Treatment with cyclobenzaprine alone had no effect on the ability of gaps to suppress the startle response. When animals were exposed to intense narrow-band (126 dB SPL, 16 kHz, 100 Hz BW) unilateral noise, GPIAS was significantly reduced, suggesting the presence of tinnitus. Following the noise exposure, a subset of rats that maintained a robust startle response continued to show GPIAS impairment at 6-20 kHz, 40 days post-noise, suggesting chronic tinnitus. When this subset of animals was treated with cyclobenzaprine, at a dose that had no significant effects on the startle response (0.5 mg/kg), GPIAS recovered partially or to near baseline levels at the affected frequencies. These results were consistent with the absence of tinnitus. By 48 h post-treatment, evidence of tinnitus re-emerged. Our results suggest that cyclobenzaprine was effective in transiently suppressing noise-induced tinnitus in rats.

Relationship between noise-induced hearing-loss, persistent tinnitus and growth-associated protein-43 expression in the rat cochlear nucleus: does synaptic plasticity in ventral cochlear nucleus suppress tinnitus?

Aberrant, lesion-induced neuroplastic changes in the auditory pathway are believed to give rise to the phantom sound of tinnitus. Noise-induced cochlear damage can induce extensive fiber growth and synaptogenesis in the cochlear nucleus, but it is currently unclear if these changes are linked to tinnitus. To address this issue, we unilaterally exposed nine rats to narrow-band noise centered at 12 kHz at 126 dB sound pressure level (SPL) for 2 h and sacrificed them 10 weeks later for evaluation of synaptic plasticity (growth-associated protein 43 [GAP-43] expression) in the cochlear nucleus. Noise-exposed rats along with three age-matched controls were screened for tinnitus-like behavior with gap prepulse inhibition of the acoustic startle (GPIAS) before, 1-10 days after, and 8-10 weeks after the noise exposure. All nine noise-exposed rats showed similar patterns of severe hair cell loss at high- and mid-frequency regions in the exposed ear. Eight of the nine showed strong up-regulation of GAP-43 in auditory nerve fibers and pronounced shrinkage of the ventral cochlear nucleus (VCN) on the noise-exposed side, and strong up-regulation of GAP-43 in the medial ventral VCN, but not in the lateral VCN or the dorsal cochlear nucleus. GAP-43 up-regulation in VCN was significantly greater in Noise-No-Tinnitus rats than in Noise-Tinnitus rats. One Noise-No-Tinnitus rat showed no up-regulation of GAP-43 in auditory nerve fibers and only little VCN shrinkage, suggesting that auditory nerve degeneration plays a role in tinnitus generation. Our results suggest that noise-induced tinnitus is suppressed by strong up-regulation of GAP-43 in the medial VCN. GAP-43 up-regulation most likely originates from medial olivocochlear neurons. Their increased excitatory input on inhibitory neurons in VCN may possibly reduce central hyperactivity and tinnitus.